DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-19, 21 and 22 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the invention of Group 1, claims 1-10, 13, 17, 18, to a protease variant, in the paper of 11/11/2025, is acknowledged. Applicant's election without traverse of the following species:
Species Group 1: X215K.
Species Group 2: X99F,X101 L, and X215K.
Species Group 3: X76D, X209W, L262E (X262E).
Species Group 4: X9E, X43R, X76D, X99F, X101L, X103T, X1041, X2051, X206L, X209W, X215K, X259D, X261W, and X262E.
Species Group 5: X97D.
Species Group 6: X161R.
Species Group 7: polyester degrading activity,
in the paper of 711/11/2025, is acknowledged
Claims 9, 10, 11, 12, 14-16, 19, 21 and 22 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms: TWEEN (paragraphs [page 59, lines 36 and 37), SPAN (paragraphs [page 59, lines 36 and 37), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Applicants filing of information disclosure statements on 2/28/20 are acknowledged and have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1-8 and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim(s) 1-8 and 13 are directed to all protease variants having a sequence identity of a mere 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, encompassed by these claims. The specification, however, only provides the representative species of that protease variant of SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these amylase variants by any identifying structural characteristics or properties, for which no predictability of structure is apparent.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim(s) 1-8 and 13 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that protease variant of SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, does not reasonably provide enablement for all possible protease variant having a sequence identity of at least 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claim(s) 1-8 and 13 are so broad as to encompass all possible protease variant having a sequence identity of at least 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2. The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of recombinant proteases broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the variant proteases encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to that protease variant of SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass any possible protease variant having a sequence identity of at least 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, because the specification does not establish: (A) regions of the protease which may be modified effecting the protease and/or polyester degrading activity; (B) the general tolerance of proteases to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of protease with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required protease and/or polyester degrading activity and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see, Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those protease variants of the claimed genus.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any protease variant having a sequence identity of at least 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those protease variants having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Closest Prior Art:
US 6,946,128 discloses a subtilisin protease comprising substitutions at positions 99, 101 and 215 relative to SEQ ID NO:2, but does not teach said substitutions in the background of SEQ ID NO:1.
Remarks
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (571) 272-0956. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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rgh
8/6/2025
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652